Immunological Basis of Genesis of Hepatocellular Carcinoma: Unique Challenges and Potential Opportunities through Immunomodulation

A majority of hepatocellular carcinoma (HCC) develops in the setting of persistent chronic inflammation as immunological mechanisms have been shown to play a vital role in the initiation, growth and progression of tumours. The index review has been intended to highlight ongoing immunological changes in the hepatic parenchyma responsible for the genesis and progression of HCC. The in-situ vaccine effect of radiofrequency (RF) is through generation tumour-associated antigens (TAAs), following necrosis and apoptosis of tumour cells, which not only re-activates the antitumour immune response but can also act in synergism with checkpoint inhibitors to generate a superlative effect with intent to treat primary cancer and distant metastasis. An improved understanding of oncogenic responses of immune cells and their integration into signaling pathways of the tumour microenvironment will help in modulating the antitumour immune response. Finally, we analyzed contemporary literature and summarised the recent advances made in the field of targeted immunotherapy involving checkpoint inhibitors along with RF application with the intent to reinstate antitumour immunity and outline future directives in very early and early stages of HCC.

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The Abscopal Effect: Could a Phenomenon Described Decades Ago Become Key to Enhancing the Response to Immune Therapies in Breast Cancer?

Breast Care ◽

10.1159/000511431 ◽

2020 ◽

Vol 15 (5) ◽

pp. 443-449

Author(s):

Hans-Christian Kolberg ◽

Oliver Hoffmann ◽

René Baumann

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Antitumor Immune Response ◽

Abscopal Effect ◽

Antitumor Effects ◽

Effective Combination ◽

Immunological Mechanisms ◽

Immune Therapies

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

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Improvement of immune response after radiofrequency ablation in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.102 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 102-102 ◽

Cited By ~ 2

Author(s):

Katia Lemdani ◽

Nathalie Mignet ◽

Johanne Seguin ◽

Frederique Peschaud ◽

Jean-François Emile ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

Radiofrequency Ablation ◽

T Lymphocytes ◽

Immune Escape ◽

Liver Tumors ◽

Residual Disease ◽

Checkpoint Inhibitors ◽

T Cell Response

102 Background: Radiofrequency ablation (RFA) efficiency of liver tumors is compromised by high rates of relapse. Death of cancer cells by hyperthermia induced tumor antigen releasing, expression of danger signals that activate a specific T-cell response. This effect is ineffective to avoid recurrence. We propose to combine RFA with priming of a strong immune antitumor response as curative treatment of an aggressive colorectal cancer (CRC) in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor as primary lesion. In two distinct clinical situations, macroscopic or microscopic distant tumors were established as secondary lesions. The immune response was modulated by the injection, in the treated area, of a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting recruitment and maturation of dendritic cells. In mice with far large lesions, this strategy was combined with PD1checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of tumoral lymphocyte infiltration TNF-α and IFN-y expression in peripheral T lymphocytes. Results: The in situ immunogel injection after RFA resulted in prolonged survival of mice. Regression of distant lesions was related to the induction of a strong systemic antitumor immune response and a great improvement of tumor infiltration by CD3+ T lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without another treatment. Immune escape of large secondary lesions was reversed by association of the RFA-immunogel vaccination with a systemic immune checkpoint inhibition, separately ineffective. Conclusions: Validation of this strategy, combining RFA of macroscopic lesions and activation of a strong immune response controlling the residual disease, could result in the design of a clinical assay including this approach within a standard treatment of colorectal liver metastases. The synergy between in situ immunomodulation as priming process and checkpoint blockade, ineffective alone in metastatic microsatellite stable CRC or after single RFA, allows reconsidering the use of checkpoint inhibitors in CRC.

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BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions

Cancers ◽

10.3390/cancers12071823 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1823 ◽

Cited By ~ 5

Author(s):

Ilaria Proietti ◽

Nevena Skroza ◽

Simone Michelini ◽

Alessandra Mambrin ◽

Veronica Balduzzi ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Tumour Microenvironment ◽

Mitogen Activated Protein Kinase ◽

Braf Inhibitors ◽

Immunomodulatory Effects ◽

Cytokine Levels ◽

Braf Mutant

The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma.

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Granzyme B PET Imaging Stratifies Immune Checkpoint Inhibitor Response in Hepatocellular Carcinoma

Molecular Imaging ◽

10.1155/2021/9305277 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Julian L. Goggi ◽

Boominathan Ramasamy ◽

Yun Xuan Tan ◽

Siddesh V. Hartimath ◽

Jun Rong Tang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nk Cells ◽

Immune Cells ◽

Immune Checkpoint ◽

T Regulatory Cells ◽

Checkpoint Inhibitors ◽

Granzyme B ◽

Tumour Volume ◽

Tumour Microenvironment

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [18F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [18F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [18F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [18F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment.

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The anti-tumour immune response after radiofrequency ablation of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14540 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14540-e14540

Author(s):

Katia Lemdani ◽

Claude Capron ◽

Johanne Seguin ◽

Nathalie Mignet ◽

Vincent Boudy ◽

...

Keyword(s):

Immune Response ◽

Radiofrequency Ablation ◽

Immune Checkpoint ◽

Tumor Antigens ◽

Immune Escape ◽

Liver Tumors ◽

Residual Disease ◽

Checkpoint Inhibitors ◽

Strong Immune Response

e14540 Background: Results of radiofrequency ablation (RFA), increasingly used to treat liver tumors, are compromised by local and systemic relapse. Hyperthermia related cancer cells death, release of tumor antigens and expression of danger signals activate a tumor-specific T-cells response. This effect remains ineffective to avoid recurrence. Therefore we propose to combine RFA with an activation of a solid immune antitumor response as curative treatment of a colorectal (CRC) metastatic disease in immunocompetent mouse. Methods: RFA was used to treat a CT26- luc tumor. In two distinct clinical situations, distant macroscopic or microscopic tumors were established as metastases before or at the time of RFA. Immune response was modulated by an injection in situof a thermo-reversible hydrogel loaded by GM-CSF and BCG, targeting dendritic cells. In the group of mice with large far lesions this strategy was combined with immune checkpoint inhibition. The efficiency was assessed on survival, evolution of distant lesions, characterization of lymphocyte infiltration in tumors and systemic immunity through specific TNF- α and IFN-y expression in spleen and draining lymph nodes. Results: The in situ immunogel injection after RFA resulted in a prolonged survival of mice. Regression of distant lesions was related to a strong systemic antitumor immune response and a great improvement of tumor infiltration by specific cytotoxic lymphocytes. In adjuvant situation, the use of immunogel induced a complete cure of microscopic secondary lesions without any treatment. Immune escape of large secondary lesions was reversed by association of RFA-immunogel vaccination with a systemic check point blockade, separately ineffective. Conclusions: Validation of this strategy, combining RFA of liver metastases and activation of a strong immune response controlling the residual disease, could result in a clinical assay including this approach within the standard treatment of CRC. Furthermorethe powerful synergy between RFA-in situ immunomodulation as a starter treatment and checkpoint blockade ineffective alone in CRC or after single RFA, allows reconsidering the use of immune checkpoint inhibitors in metastatic microsatellite stable CRC.

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Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma

Current Medicinal Chemistry ◽

10.2174/0929867327666201013162144 ◽

2020 ◽

Vol 27 ◽

Author(s):

Tao Wang ◽

Qiting Zhang ◽

Ning Wang ◽

Ziqi Liu ◽

Bin Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Targeted Therapy ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Modern Medicine ◽

Vital Role ◽

Research Progress ◽

Molecular Targeting Drug ◽

Further Development ◽

Made In

: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.

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The Role of Protein SUMOylation in Human Hepatocellular Carcinoma: A Potential Target of New Drug Discovery and Development

Cancers ◽

10.3390/cancers13225700 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5700

Author(s):

Hongchao Yuan ◽

Yuanjun Lu ◽

Yau-Tuen Chan ◽

Cheng Zhang ◽

Ning Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle Progression ◽

Critical Role ◽

Tumour Microenvironment ◽

Vital Role ◽

Hepatic Tissue ◽

Post Translational Modification ◽

Cycle Progression ◽

Potential Target

Small ubiquitin-like modifier (SUMO) is a highly conserved post-translational modification protein, mainly found in eukaryotes. They are widely expressed in different tissues, including the liver. As an essential post-translational modification, SUMOylation is involved in many necessary regulations in cells. It plays a vital role in DNA repair, transcription regulation, protein stability and cell cycle progression. Increasing shreds of evidence show that SUMOylation is closely related to Hepatocellular carcinoma (HCC). The high expression of SUMOs in the inflammatory hepatic tissue may lead to the carcinogenesis of HCC. At the same time, SUMOs will upregulate the proliferation and survival of HCC, migration, invasion and metastasis of HCC, tumour microenvironment as well as drug resistance. This study reviewed the role of SUMOylation in liver cancer. In addition, it also discussed natural compounds that modulate SUMO and target SUMO drugs in clinical trials. Considering the critical role of SUMO protein in the occurrence of HCC, the drug regulation of SUMOylation may become a potential target for treatment, prognostic monitoring and adjuvant chemotherapy of HCC.

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Tune Up In Situ Autovaccination against Solid Tumors with Oncolytic Viruses

10.20944/preprints201804.0359.v1 ◽

2018 ◽

Author(s):

Teresa Nguyen ◽

Naze G. Avci ◽

Dong Ho Shin ◽

Naiara Martinez-Velez ◽

Hong Jiang

Keyword(s):

Immune Response ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Molecular Patterns ◽

Cell Inhibition ◽

Damage Associated Molecular Patterns

With the progress of immunotherapy in cancer, oncolytic viruses (OVs) are getting more and more attention during the past decade. Due to their cancer-selective and immunogenic property, OVs are considered ideal candidates to be combined with immunotherapy to increase both specificity and efficacy in cancer treatment. OVs preferentially replicate in and lyse cancer cells, generating pathogen-associated molecular patterns (PAMPs) and danger (damage)-associated molecular patterns (DAMPs). These signals trigger innate immune response to modulate the solid tumor microenvironment, resulting in in situ autovaccination leading to adaptive anti-virus and anti-tumor immunity. Here, we summarize the conceptual updates of oncolytic virotherapy, immunotherapy, and the strategies to enhance the virus-mediated anti-tumor immune response, including: 1. Arm OVs with cytokines to modulated innate and adaptive immunity; 2. Combine OVs with immune checkpoint inhibitors to release T cell inhibition; 3. Combine OVs with immune co-stimulators to enhance T cell activation.

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Outcome of Initial Progression During Nivolumab Treatment for Hepatocellular Carcinoma: Should We Use iRECIST?

Frontiers in Medicine ◽

10.3389/fmed.2021.771887 ◽

2021 ◽

Vol 8 ◽

Author(s):

Dong Ho Lee ◽

Sangyoun Hwang ◽

Young Hwan Koh ◽

Kyung-Hun Lee ◽

Ju Yeon Kim ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Response ◽

Multicenter Study ◽

Immune Checkpoint Inhibitors ◽

Progressive Disease ◽

Checkpoint Inhibitors ◽

Evaluation Criteria ◽

Response Evaluation ◽

Retrospective Multicenter Study ◽

Response Evaluation Criteria

Immune response evaluation criteria in solid tumors (iRECIST) is recommended during immune checkpoint inhibitors (ICIs) treatment, due to the possibility of pseudoprogression. We evaluated the frequency of pseudoprogression in hepatocellular carcinoma (HCC) patients. This retrospective multicenter study involved 158 consecutive patients who underwent nivolumab treatment for HCC in Korea. At the initial evaluation, 94 patients presented with immune unconfirmed progressive disease, and 22 continued nivolumab. At the second evaluation, 21 of the 22 patients (95.5%) had confirmed progression and no pseudoprogression was observed. Considering low possibility of pseudoprogression, iRECIST may not be required for HCC.

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In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.650486 ◽

2021 ◽

Vol 12 ◽

Author(s):

Isabella Lurje ◽

Wiebke Werner ◽

Raphael Mohr ◽

Christoph Roderburg ◽

Frank Tacke ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Antigen Presentation ◽

Tumor Cells ◽

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Oncolytic Viruses ◽

Tlr Agonists ◽

Gm Csf

Hepatocellular Carcinoma (HCC) is a highly prevalent malignancy that develops in patients with chronic liver diseases and dysregulated systemic and hepatic immunity. The tumor microenvironment (TME) contains tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) and is central to mediating immune evasion and resistance to therapy. The interplay between these cells types often leads to insufficient antigen presentation, preventing effective anti-tumor immune responses. In situ vaccines harness the tumor as the source of antigens and implement sequential immunomodulation to generate systemic and lasting antitumor immunity. Thus, in situ vaccines hold the promise to induce a switch from an immunosuppressive environment where HCC cells evade antigen presentation and suppress T cell responses towards an immunostimulatory environment enriched for activated cytotoxic cells. Pivotal steps of in situ vaccination include the induction of immunogenic cell death of tumor cells, a recruitment of antigen-presenting cells with a focus on dendritic cells, their loading and maturation and a subsequent cross-priming of CD8+ T cells to ensure cytotoxic activity against tumor cells. Several in situ vaccine approaches have been suggested, with vaccine regimens including oncolytic viruses, Flt3L, GM-CSF and TLR agonists. Moreover, combinations with checkpoint inhibitors have been suggested in HCC and other tumor entities. This review will give an overview of various in situ vaccine strategies for HCC, highlighting the potentials and pitfalls of in situ vaccines to treat liver cancer.

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